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Multiple sclerosis (MS) and Devic's disease (also known as Neuromyelitis Optica [NMO]) are inflammatory neurodegenerative disorders that affect the central nervous system (CNS). They are caused by autoimmune attack in which inflammatory cells invade the nervous system leading to demyelination and tissue destruction (Morales et al, Adv Neurol 98:27-45, 2006). This destruction and demyelination leads to impairment of cognitive function and higher mortality (Bergamaschi et al, Neuroepidemiology 25 (1):15-8, 2005; Ragonese et al, Eur J Neurol 15 (2):123-7, 2008). MS is more common in women than men, affecting approximately 3 people per 100,000 (Alonso et al, Neurology 71 (2):129-35, 2008) and can be categorized into either relapsing remitting (majority of cases) or rapidly progressing (minority [10%]) forms. Currently, there is no cure for either form of the disease. Standard therapies for neurological inflammation include recombinant interferon treatment and immunosuppressive agents such as methylprednisolone or methotrexate (Lopez-Diego et al, Nat Rev Drug Discov 7 (11):909-25, 2008). These treatments reduce but do not prevent progression of the disease. There is a need to develop an efficacious treatment.
MS lesions are characterized by infiltration by a range of immune cells including T cells, macrophages, dendritic cells and neutrophils (Morales et al, 2006 supra). Similar lesions are also found in Devic's disease patients that are often more aggressive and rapidly progressing with preferential involvement of the spinal cord and optic nerves (Wingerchuk et al, Lancet Neurol 6 (9):805-15, 2007; Wingerchuk et al, Curr Treat Options Neurol 10 (1):55-66, 2008). Although both disorders are widely believed to be the result of aberrant CD4+ helper T cell responses, T cell targeted therapies have been relatively unsuccessful in the clinic (Lopez-Diego et al, 2008 supra). This has led to a renewed focused on the role of innate immune cells in neurological pathologies (Weiner et al, J Neurol 255 (Suppl 1): 3-11, 2008).
Neutrophils are one of the central innate immune effector cells and are rapidly recruited to sites of inflammation where they release damaging agents such as reactive oxygen metabolites. They can be found along with other immune cells infiltrating the nervous system in both MS and Devic's disease patients. Lesional tissue and cerebrospinal fluid from Devic's disease patients (who have often been diagnosed as having a poor prognosis) are particularly neutrophil rich (Wingerchuk et al, 2007; 2008; supra). However, the role of neutrophils in CNS pathologies remains unclear. Neutrophils have been suggested in the literature as having either a protective role or a pathogenic role in animal models of CNS autoimmune inflammation. Depleting neutrophils with a neutrophil specific monoclonal antibody in a mouse model of MS reduced disease severity (McColl et al, J Immunol 161 (11):6421-6, 1998). On the other hand, other researchers investigating neutrophils in a mouse model of MS found that neutrophils isolated from the CNS are effective T cell suppressors (Zehntner et al, J Immunol 174 (8):5124-31, 2005).
One cytokine involved in inflammatory reactions is granulocyte colony-stimulating factor (G-CSF) which is encoded by the CSF-3 gene. G-CSF is a hemopoietic growth factor that regulates the production of granulocytes (Nicola et al, Nature 314:625, 1985; Metcalf, International Journal of Cancer 25:225, 1980; Nicola et al, Journal of Biological Chemistry 258:9017, 1983). G-CSF mediates its effects through interaction with the G-CSF receptor (G-CSFR, encoded by the CSFR-3 gene), a member of the type I cytokine receptor superfamily (Demetri et al, Blood 78:2791-2808, 1991). Major biological actions of G-CSF in humans and mice include increasing the production and release of neutrophils from the bone marrow (Souza et al, Science 232:61, 1986; Lord et al, Proc. Natl. Acad. Sci. USA 86:9499-9503, 1989), mobilizing hemopoietic progenitor cells from the marrow into the peripheral blood (Bungart et al, British Journal of Haematology 22:1156, 1990; de Haan et al, Blood 86:2986-2992, 1995; Roberts et al, Blood 89:2736-2744, 1997) and modulating the differentiation and effector functions of mature neutrophils (Yong et al, European Journal of Haematology 49:251-259, 1992; Colotta et al, Blood 80:2012-2020, 1992; Rex et al, Transfusion 35:605-611, 1995; Gericke et al, Journal of Leukocyte Biology 57:455-461, 1995; Xu et al, British Journal of Haematology 93:558-568, 1996; Yong, British Journal of Haematology 94:40-47, 1996; Jacob et al, Blood 92:353-361, 1998). G-CSF also acts on mature postmitotic neutrophils after they leave the bone marrow including having effects on phagocytosis (Bialek et al, Infection 26 (6):375-8, 1998), apoptosis (Dibbert et al, Proc Natl Acad Sci USA 96 (23):13330-5, 1999) and homing (Dagia et al, Nat Med 12 (10):1185-90, 2006; Eyles et al, Blood 112 (13):5193-201, 2008). G-CSF is used to treat neutropenia, as well as to induce mobilization of hemopoietic stem cells (HSC) for autologous and allogenic stem cell transplantation (Welte et al, Blood 88:1907-1929, 1996).
As outlined above, there is experimental evidence with neutrophil depleting antibodies that support a pro-inflammatory function for the G-CSF/neutrophil axis in MS. In addition, clinical case studies have reported that some patients treated with G-CSF display a worsening of clinical symptoms (Openshaw et al, “Neurology 54 (11):2147-50, 2000; Snir et al, J Neuroimmunol 172 (1-2):145-55, 2006). However, these reports are relatively rare and significant evidence exists supporting an anti-inflammatory role for G-CSF in CNS disease conditions. In the experimental autoimmune encephalomyelitis (EAE) animal model of MS, treatment with systemic and local (CNS) delivered G-CSF alleviates disease (Zavala et al, J Immunol 168 (4):2011-9, 2002). This is consistent with the T cell tolerizing (Rutella et al, Transplantation 84 (1 Suppl):S26-30, 2007) and neuroprotective role (Frank et al, BMC Neurosci 10:49, 2009) prescribed to G-CSF by others. In addition, the anti-inflammatory properties of G-CSF have been well documented in other autoimmune diseases such as type I diabetes (Hadaya et al, J Autoimmun 24 (2):125-34, 2005) and inflammatory bowel disease (Kudo et al, Scand J Gastroenterol 43 (6):689-97, 2008). In fact, recombinant human G-CSF has even been used in the clinic to treat inflammatory bowel disease (Barahona-Gamido et al, Biologics 2 (3):501-4, 2008). Hence, G-CSF is a pleiotropic cytokine having a multiplicity of roles.
There is a need to develop new treatments for inflammatory neurodegenerative conditions in the CNS such as MS, Devic's disease and viral infections of the brain.